Pulmonary vascular medial hypertrophy in patients with primary pulmonary hypertension (PPH) is mainly due to increased pulmonary artery smooth muscle cell (PASMC) growth and/or decreased PASMC apoptosis. The precise control of the balance between PASMC proliferation and apoptosis plays a critical role in maintaining the structural integrity of the pulmonary vasculature. Activation of apoptosis is implicated in the regression of pulmonary vascular medial hypertrophy, whereas inhibition of apoptosis leads to the progression of pulmonary vascular wall thickening. Cell volume decrease is an early hallmark of apoptosis. Maintenance of a high concentration of cytosolic K+ ([K+]cyt) is essential to the regulation of normal ion homeostasis and cell volume, and to the suppression of cytoplasmic caspases. Thus, activation of K+ channels induces apoptotic volume decrease (AVD) and apoptosis by enhancing K +loss, whereas inhibition of K+ channel activity attenuates AVD by maintaining sufficient [K+]cyt to inhibit apoptosis. ? ? In normal PASMC, our preliminary data demonstrate that apoptosis inducers, such as staurosporine (ST) and cytochrome c, increased K+ channel activity, whereas anti-apoptotic proteins (e.g., Bcl-2) decreased K+ channel activity. Pharmacological blockade of voltage-gated K+(Kv) channels attenuated ST-induced apoptosis. Furthermore, expression and function of Kv channels were markedly reduced in PASMC from PPH patients in comparison to PASMC from normal subjects and patients with secondary pulmonary hypertension (SPH). The ST-induced apoptosis was also significantly inhibited in PPH-PASMC in comparison to SPH-PASMC. Based on these data, we hypothesize that inhibition of apoptosis in PASMC as a result of down regulation and dysfunction of Kv channels plays an critical role in the development of pulmonary vascular medial hypertrophy in PPH.
Three Specific Aims are addressed to test the hypothesis: 1) To investigate the role of Kv channels in the development of AVD and apoptosis and to identify Kv channel subtypes that are involved in regulating cell volume in normal human PASMC; 2) To determine the effects of pro-apoptotic and anti-apoptotic proteins on Kv channel expression and function in human PASMC; and 3) To determine whether apoptosis is inhibited in PPH-PASMC and if so, what cellular and molecular mechanisms are responsible for the inhibited apoptosis. ? ?
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